细胞生长抑制剂Dolastatin 15类似物的合成及其活性研究  

Synthesis of Cell Growth Inhibitor Dolastatin 15 Analogues and Their Activities

作　　者：郄建坤[1] 梁远军[1] 吴萍[1] 何军林[1] 赵修南[1] 周文霞[1] 张永祥[1] 刘克良[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850

出　　处：《高等学校化学学报》2009年第2期308-313,共6页Chemical Journal of Chinese Universities

摘　　要：通过在细胞生长抑制剂Dolastatin15(D15)的N端引入含环胺基的非天然氨基酸1～3,赋予其构象限制和疏水性,设计合成了21个结构类似物,并进行了体外抑制肿瘤细胞生长的活性评价.结果表明,部分化合物显示出较好的抑制肿瘤细胞生长活性,同时探讨了初步的构效关系.Dolastatin 15 （D15）was a linear depsipeptide with two N-methylated valines and a complex C-terminal, showing potent cell growth inhibitory activity. D15 was highly alkylation and with spacial constraints. Modifications at D15＇s N-terminal were performed by introducing three unnatural amino acid analogs 1--3 with more conformation-restriction and hydrophobicity. Twenty-one compounds were synthesized, and their activities were evaluated in vitro on human tumor cell lines K562, OVCA2780 and Kato-Ⅲ. Some compounds exhibited modest potency compared to compound LU103793, an analog of D15, evaluated in clinical phase Ⅱ now. A primary structure-activity relationship was summarized about the N-terminal.

关 键 词：细胞生长抑制剂 Dolastatin 15类似物 线性肽 海洋生物活性肽 

分 类 号：O629[理学—有机化学]